Oral tolerance (OT) is defined as the state of immunologic unresponsiveness induced by the prior feeding of antigen. OT has been demonstrated repeatedly in rodents, in which it can effectively down regulate experimental autoimmune diseases. Because OT has never been formally demonstrated in man, volunteers were fed the protein antigen, keyhole limpet hemocyanin (KLH). KLH feeding may have had differential effects on Th1 vs Th2 subsets. In studies planned in this application it is proposed to define the parameters required for the induction of tolerance to KLH, using it as a prototypic mucosal tolerogen. Large vs. small doses of antigen will be used to determine whether anergy vs suppression will be preferentially induced (Specific Aim 1). The phenotype of circulating T cells that respond to KLH and their cytokine profiles will be determined with respect to a differential effect on Th1 vs. Th2 CD4+ T cells, and TGF production after antigen feeding in humans as a potential mechanism for oral tolerance (Specific Aim 2). Not all proteins cause oral tolerance; at the other endo for the spectrum are proteins such as cholera toxin B subunit (CT-B), that induce both systemic and mucosal immunogen will be determined and the results compared to those obtained after the feeding of KLH. Moreover, the ability of CT-B fed together wit KLH to abrogate OT to KLH or induce immunity to it will be determine (Specific Aim 3). Humans ingest daily large amounts of antigens in the form of food, and this thus represents a "natural" form of oral tolerance. Selected individuals can be separated into high vs low responders for a food antigen such as ovalbumin (OVA) on the basis of serum antibody are tolerant, but those with high serum antibody are not. These two groups will be tested both before and after a challenge dose of OVA and the responding cells and their pattern of cytokine secretion will be identified. Moreover, the hypothesis that T cells from high vs low responder individuals recognize different epitopes on OVA will be tested (Specific Aim 4). It is possible that the response to food antigens may be predictive of a substantially to our understanding of oral tolerance and immunity in humans. The overall goal is to identify the cellular and molecular mechanisms of oral tolerance and immunity so that each can be optimally exploited in order to maintain health and treat disease.